11-103148531-G-A

Position:

• chr11-103148531-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000375735.7(DYNC2H1):​c.2860G>A​(p.Glu954Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0148 in 1,565,512 control chromosomes in the GnomAD database, including 226 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E954E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (18 hom., cov: 33)
  • Exomes 𝑓: 0.015 (208 hom.)
• Consequence: DYNC2H1 ENST00000375735.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.92

Genes affected

DYNC2H1 (HGNC:2962): (dynein cytoplasmic 2 heavy chain 1) This gene encodes a large cytoplasmic dynein protein that is involved in retrograde transport in the cilium and has a role in intraflagellar transport, a process required for ciliary/flagellar assembly. Mutations in this gene cause a heterogeneous spectrum of conditions related to altered primary cilium function and often involve polydactyly, abnormal skeletogenesis, and polycystic kidneys. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026997924).
• BP6: Variant 11-103148531-G-A is Benign according to our data. Variant chr11-103148531-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 188134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-103148531-G-A is described in Lovd as [Likely_benign]. Variant chr11-103148531-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0122 (1860/152220) while in subpopulation SAS AF= 0.0233 (112/4814). AF 95% confidence interval is 0.0198. There are 18 homozygotes in gnomad4. There are 907 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 18 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC2H1	NM_001080463.2	c.2860G>A	p.Glu954Lys	missense_variant	20/90	ENST00000650373.2	NP_001073932.1
DYNC2H1	NM_001377.3	c.2860G>A	p.Glu954Lys	missense_variant	20/89	ENST00000375735.7	NP_001368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC2H1	ENST00000650373.2	c.2860G>A	p.Glu954Lys	missense_variant	20/90		NM_001080463.2	ENSP00000497174	A1
DYNC2H1	ENST00000375735.7	c.2860G>A	p.Glu954Lys	missense_variant	20/89	1	NM_001377.3	ENSP00000364887	P3

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1857 AN: 152102 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.00290

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0142

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0237

Gnomad FIN AF: 0.0176

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0169

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.0163 AC: 2931 AN: 179972 Hom.: 58 AF XY: 0.0162 AC XY: 1546 AN XY: 95452

Gnomad AFR exome AF: 0.00298

Gnomad AMR exome AF: 0.0306

Gnomad ASJ exome AF: 0.00422

Gnomad EAS exome AF: 0.000152

Gnomad SAS exome AF: 0.0229

Gnomad FIN exome AF: 0.0128

Gnomad NFE exome AF: 0.0162

Gnomad OTH exome AF: 0.0134

GnomAD4 exome AF: 0.0150 AC: 21240 AN: 1413292 Hom.: 208 Cov.: 30 AF XY: 0.0154 AC XY: 10736 AN XY: 698332

Gnomad4 AFR exome AF: 0.00235

Gnomad4 AMR exome AF: 0.0284

Gnomad4 ASJ exome AF: 0.00369

Gnomad4 EAS exome AF: 0.0000802

Gnomad4 SAS exome AF: 0.0238

Gnomad4 FIN exome AF: 0.0131

Gnomad4 NFE exome AF: 0.0152

Gnomad4 OTH exome AF: 0.0136

GnomAD4 genome AF: 0.0122 AC: 1860 AN: 152220 Hom.: 18 Cov.: 33 AF XY: 0.0122 AC XY: 907 AN XY: 74416

Gnomad4 AFR AF: 0.00289

Gnomad4 AMR AF: 0.0145

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0233

Gnomad4 FIN AF: 0.0176

Gnomad4 NFE AF: 0.0169

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.0154 Hom.: 32

Bravo AF: 0.0113

TwinsUK AF: 0.0146 AC: 54

ALSPAC AF: 0.0122 AC: 47

ESP6500AA AF: 0.00356 AC: 13

ESP6500EA AF: 0.0145 AC: 118

ExAC AF: 0.0112 AC: 1329

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Jeune thoracic dystrophy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Asphyxiating thoracic dystrophy 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	.;T;T;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	0.035
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.76	T;.;T;.;T
MetaRNN	Benign	0.0027	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	.;L;L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.8	.;D;.;.;D
REVEL	Benign	0.080
Sift	Benign	0.088	.;T;.;.;T
Sift4G	Benign	0.16	.;T;.;.;T
Polyphen		0.0, 0.0010	.;B;B;B;B
Vest4		0.086, 0.074
MPC		0.069
ClinPred		0.024	T
GERP RS		4.7
Varity_R		0.099
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61898615; hg19: chr11-103019260;